Therapeutic agent delivery device with controlled therapeutic agent release rates

ABSTRACT

The present invention relates to implantable medical devices for the localized delivery of therapeutic agents, such as drugs, to a patient. More particularly, the invention relates to a device having a gradient of water soluble therapeutic agents within a therapeutic agent layer and a mixing layer that allows for controlled release of the therapeutic agents.

FIELD OF THE INVENTION

[0001] The invention relates to a therapeutic agent delivery devicewhich comprises a gradient of therapeutic agent within mixing layerswhich provides for the controlled release of water soluble therapeuticagents.

DESCRIPTION OF THE RELATED ART

[0002] Implantable medical devices are often used for delivery of abeneficial agent, such as a drug, to an organ or tissue in the body at acontrolled delivery rate over an extended period of time. These devicesmay deliver agents to a wide variety of bodily systems to provide a widevariety of treatments.

[0003] One of the many implantable medical devices which have been usedfor local delivery of beneficial agents is the coronary stent. Coronarystents are typically introduced percutaneously, and transportedtransluminally until positioned at a desired location. These devices arethen expanded either mechanically, such as by the expansion of a mandrelor balloon positioned inside the device, or expand themselves byreleasing stored energy upon actuation within the body. Once expandedwithin the lumen, these devices, called stents, become encapsulatedwithin the body tissue and remain a permanent implant.

[0004] Known stent designs include monofilament wire coil stents (U.S.Pat. No. 4,969,458); welded metal cages (U.S. Pat. Nos. 4,733,665 and4,776,337); and, most prominently, thin-walled metal cylinders withaxial slots formed around the circumference (U.S. Pat. Nos. 4,733,665;4,739,762; and 4,776,337). Known construction materials for use instents include polymers, organic fabrics and biocompatible metals, suchas stainless steel, gold, silver, tantalum, titanium, and shape memoryalloys, such as Nitinol.

[0005] Of the many problems that may be addressed through stent-basedlocal delivery of beneficial agents, one of the most important isrestenosis. Restenosis is a major complication that can arise followingvascular interventions such as angioplasty and the implantation ofstents. Simply defined, restenosis is a wound healing process thatreduces the vessel lumen diameter by extracellular matrix deposition,neointimal hyperplasia, and vascular smooth muscle cell proliferation,and which may ultimately result in renarrowing or even reocclusion ofthe lumen. Despite the introduction of improved surgical techniques,devices, and pharmaceutical agents, the overall restenosis rate is stillreported in the range of 25% to 50% within six to twelve months after anangioplasty procedure. To treat this condition, additionalrevascularization procedures are frequently required, thereby increasingtrauma and risk to the patient.

[0006] One of the techniques under development to address the problem ofrestenosis is the use of surface coatings of various beneficial agentson stents. U.S. Pat. No. 5,716,981, for example, discloses a stent thatis surface-coated with a composition comprising a polymer carrier andpaclitaxel (a well-known compound that is commonly used in the treatmentof cancerous tumors). The patent offers detailed descriptions of methodsfor coating stent surfaces, such as spraying and dipping, as well as thedesired character of the coating itself: it should “coat the stentsmoothly and evenly” and “provide a uniform, predictable, prolongedrelease of the anti-angiogenic factor.” Surface coatings, however, canprovide little actual control over the release kinetics of beneficialagents. These coatings are necessarily very thin, typically 5 to 8microns deep. The surface area of the stent, by comparison is verylarge, so that the entire volume of the beneficial agent has a veryshort diffusion path to discharge into the surrounding tissue.

[0007] Increasing the thickness of the surface coating has thebeneficial effects of improving drug release kinetics including theability to control drug release and to allow increased drug loading.However, the increased coating thickness results in increased overallthickness of the stent wall. This is undesirable for a number ofreasons, including increased trauma to the vessel wall duringimplantation, reduced flow cross-section of the lumen afterimplantation, and increased vulnerability of the coating to mechanicalfailure or damage during expansion and implantation. Coating thicknessis one of several factors that affect the release kinetics of thebeneficial agent, and limitations on thickness thereby limit the rangeof release rates, duration of drug delivery, and the like that can beachieved.

[0008] In addition to sub-optimal release profiles, there are furtherproblems with surface coated stents. The fixed matrix polymer carriersfrequently used in the device coatings typically retain approximately30% of the beneficial agent in the coating indefinitely. Since thesebeneficial agents are frequently highly cytotoxic, sub-acute and chronicproblems such as chronic inflammation, late thrombosis, and late orincomplete healing of the vessel wall may occur. Additionally, thecarrier polymers themselves are often highly inflammatory to the tissueof the vessel wall. On the other hand, use of biodegradable polymercarriers on stent surfaces can result in the creation of “virtualspaces” or voids between the stent and tissue of the vessel wall afterthe polymer carrier has degraded, which permits differential motionbetween the stent and adjacent tissue. Resulting problems includemicro-abrasion and inflammation, stent drift, and failure tore-endothelialize the vessel wall.

[0009] Another significant problem is that expansion of the stent maystress the overlying polymeric coating causing the coating toplastically deform or even to rupture, which may therefore effect drugrelease kinetics or have other untoward effects. Further, expansion ofsuch a coated stent in an atherosclerotic blood vessel will placecircumferential shear forces on the polymeric coating, which may causethe coating to separate from the underlying stent surface. Suchseparation may again have untoward effects including embolization ofcoating fragments causing vascular obstruction.

[0010] In addition, it is not currently possible to deliver some drugswith a surface coating for a variety of reasons. In some cases, thedrugs are sensitive to water, other compounds, or conditions in the bodywhich degrade the drugs. For example, some drugs lose substantially alltheir activity when exposed to water for a period of time. When thedesired treatment time is substantially longer than the half life of thedrug in water the drug cannot be delivered by know coatings. Otherdrugs, such as protein or peptide based therapeutic agents, loseactivity when exposed to enzymes, pH changes, or other environmentalconditions. And finally drugs that are highly-soluble in water tend tobe released from the coatings at an undesirably high rate and do notremain localized for a therapeutically useful amount of time. Thesetypes of drugs which are sensitive to compounds or conditions in thebody often cannot be delivered using surface coatings.

[0011] Accordingly, it would be desirable to provide a beneficial agentdelivery device for delivery of agents, such as drugs, to a patientwhile protecting the agent from compounds or conditions in the bodywhich would degrade the agent.

SUMMARY OF THE INVENTION

[0012] The present invention relates to medical device for thecontrolled delivery of therapeutic agents where the release of thetherapeutic agent is mediated by a mixing layer.

[0013] In one of its device aspects the present invention provides foran implantable medical device comprising an implantable device bodyhaving a plurality of holes; a therapeutic agent provided in a firsttherapeutic agent layer and contained within the plurality of holes inthe device body; and at least one mixing layer provided adjacent thefirst therapeutic agent layer in the plurality of holes; wherein thetherapeutic agent layer and the at least one mixing layer togethercontain a concentration gradient of said therapeutic agent and allow forthe controlled release of the therapeutic agent contained within thetherapeutic agent layer and the at least one mixing layer.

[0014] In another of its device aspects the present invention providesfor an implantable medical device comprising an implantable device bodyhaving a plurality of holes; a therapeutic agent within the plurality ofholes in the device body provided in a therapeutic agent layer; and amixing layer provided in the plurality of holes; wherein the therapeuticagent layer and the mixing layer contain a concentration gradient ofsaid therapeutic agent created by delivering a mixing layer materialwithout the therapeutic agent and liquefying a portion of thetherapeutic agent layer with the mixing layer material, whereby themixing layer has a lesser amount of therapeutic agent contained thereinthan the therapeutic agent layer.

[0015] The mixing layers are preferably a pharmaceutically acceptablebioresorbable matrix, more preferably pharmaceutically acceptablepolymers. Even more preferably the mixing layers are selected from thegroup consisting of polylactic acid, polyglycolic acid,polylactic-co-glycolic acid, polylactic acid-co-caprolactone,polyethylene glycol, polyethylene oxide, poly lactic acid-btock-polyethylene glycol, poly glycolic acid-block-poly ethylene glycol, polylactide-co-glycolide-block-poly ethylene glycol, poly ethyleneglycol-block-lipid, polyvinyl pyrrolidone, poly vinyl alcohol, aglycosaminoglycan, polyorthoesters, polysaccharides, polysaccharidederivatives, polyhyaluronic acid, polyalginic acid, chitin, chitosan,chitosan derivatives, cellulose, hydroxyethylcellulose,hydroxypropylcellulose, carboxymethylcellulose, polypeptides,polylysine, polyglutamic acid, albumin, polyanhydrides, polyhydroxyalkonoates, polyhydroxy valerate, polyhydroxy butyrate, proteins,polyphosphate esters, lipids, and mixtures thereof.

[0016] The therapeutic agent layer preferably comprises the therapeuticagent and a water soluble binding agent. The water soluble binding agentis preferably selected from poly ethylene glycol, poly ethylene oxide,poly vinylpyrrolidone, poly vinyl alcohol, a glycosaminoglycan,polysaccharides, polysaccharide derivatives, poly hyaluronic acid, polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, poly peptides, poly lysine, poly glutamic acid, and proteins,such as albumin.

[0017] The liquefied therapeutic agent layer comprises from about 20% toabout 95% therapeutic agent and from about 5% to about 70%pharmaceutically acceptable polymer preferably from about 50% to about95% therapeutic agent and from about 5% to about 50% pharmaceuticallyacceptable polymer, more preferably from about 50% to about 60%therapeutic agent and from about 40% to about 50% pharmaceuticallyacceptable polymer.

[0018] The therapeutic agent is preferably antithrombotic agents, aantineoplastic agent, a neoplastic agent, an antiproliferative agent, anantisense compound, an immunosuppresant, an angiogenic agent, anangiogenic factor, an antiangiogenic agent, or an anti-inflammatoryagent, or combinations thereof. More preferably the therapeutic agent isof 2-chlorodeoxyadenosine, bivalirudin, Resten NG, or anoliogonucleotide, or mixtures thereof.

[0019] The therapeutic agent maybe homogeneously or heterogeneouslydispersed in the therapeutic agent layer and/or the mixing layer(s). Thetherapeutic agent may be homogeneously or heterogeneously disposed in alayer as a solid particle dispersion, encapsulated agent dispersion, anemulsion, a suspension, a liposome, niosome, or a microparticle, whereinsaid niosome, liposome or microparticle comprise a homogeneous orheterogeneous mixture of the therapeutic agent. When a therapeutic agentis homogeneously disposed in a therapeutic agent layer, it may be asolid-solution or a multi-phase mixture.

[0020] Optionally the liquefied bioresorbable polymer loaded into theholes does not contain the therapeutic agent.

[0021] The implantable medical device is useful in the treatment ofrestenosis and inflammation and is preferably a stent.

[0022] The bioresorbable polymers, binding agents of the individuallayers may be the same or different. In one embodiment, the polymersused in the therapeutic agent layer is different than the polymer usedin the mixing layer. The polymers and binging agents of the individuallayers maybe liquified by dissolution of the materials in a solvent orby maintaining the materials at a temperature that is higher than theirmelting points, or glass transition temperatures.

[0023] The implantable medical device may optionally further comprise abarrier layer, wherein the barrier layer is located adjacent thetherapeutic agent layer. The barrier layer is formed by loading into theplurality of holes an amount of a liquified biocompatible polymer, whichamount is sufficient to form a barrier layer, wherein the barrier layeris located adjacent the therapeutic agent layer.

[0024] In one of its method aspects the present invention provides foran method for preparing an implantable medical device as describedherein above, which method comprises:

[0025] a) providing an implantable medical device with a plurality ofholes;

[0026] b) loading into the plurality of holes an amount of a liquifiedtherapeutic agent, which amount is sufficient to form a therapeuticagent layer;

[0027] c) allowing said liquified therapeutic agent layer to at leastpartially solidify;

[0028] d) loading into the plurality of holes an amount of a liquifiedbioresorbable polymer which amount is sufficient to liquify a portion ofthe therapeutic agent layer, thereby allowing a portion of thetherapeutic agent layer to be disposed within a mixing layer;

[0029] e) allowing said liquified bioresorbable polymer and said portionof the therapeutic agent layer to solidify;

[0030] wherein an amount of therapeutic agent contained within themixing layer upon solidification is smaller than an amount oftherapeutic agent contained in the therapeutic agent layer and furtherwherein steps d and e may optionally be repeated to form multiple mixinglayers.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0031] The invention will now be described in greater detail withreference to the preferred embodiments illustrated in the accompanyingdrawings, in which like elements bear like reference numerals, andwherein:

[0032]FIG. 1 is a perspective view of a therapeutic agent deliverydevice in the form of an expandable stent.

[0033]FIG. 2 is a cross sectional view of a portion of a therapeuticagent delivery device having a beneficial agent contained in an openingin layers.

DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention relates to a delivery device for deliveryof water soluble therapeutic agents to a patient. More particularly, theinvention relates to a medical device having therapeutic agentsprotected from premature release into a patient by one or more mixinglayers. Details for the device design, therapeutic agents, therapeuticagent layers, and mixing layers may also be found in U.S. patentapplication Ser. No. 10/253,020, filed on Sep. 23, 2002, incorporatedherein by reference in its entirety. First, the following terms, as usedherein, shall have the following meanings:

[0035] The term “beneficial agent” as used herein are intended to havetheir broadest possible interpretation and is used to include anytherapeutic agent or drug, as well as inactive agents such as barrierlayers, carrier layers, therapeutic layers or mixing layers.

[0036] The terms “drug” and “therapeutic agent” are used interchangeablyto refer to any therapeutically active substance that is delivered to abodily conduit of a living being to produce a desired, usuallybeneficial, effect. The present invention is particularly well suitedfor the delivery of antineoplastic, angiogenic factors,immuno-suppressants, and antiproliferatives (anti-restenosis agents)such as paclitaxel, Rapamycin or 2-chlorodeoxyadenosine, for example,and antithrombins such as heparin, for example.

[0037] The therapeutic agents used in the present invention includeclassical low molecular weight therapeutic agents commonly referred toas drugs including all classes of action as exemplified by, but notlimited to: antineoplastic, immuno-suppressants, antiproliferatives,antithrombins, antiplatelet, antilipid, anti-inflammatory, angiogenic,anti-angiogenic, vitamins, ACE inhibitors, vasoactive substances,antimitotics, metello-proteinase inhibitors, NO donors, estradiols,anti-sclerosing agents, alone or in combination. Therapeutic agent alsoincludes higher molecular weight substances with drug like effects ontarget tissue sometimes called biologic agents including but not limitedto: peptides, lipids, protein drugs, protein conjugates drugs, enzymes,oligonucleotides, ribozymes, genetic material, prions, virus, bacteria,and eucaryotic cells such as endothelial cells, monocyte/macrophages orvascular smooth muscle cells to name but a few examples. The therapeuticagent may also be a pro-drug, which metabolizes into the desired drugwhen administered to a host. In addition, the therapeutic agents may bepre-formulated as a microcapsules, microspheres, microbubbles,liposomes, niosomes, emulsions, dispersions or the like before it isincorporated into the therapeutic layer. The therapeutic agent may alsobe radioactive isotopes or agents activated by some other form of energysuch as light or ultrasonic energy, or by other circulating moleculesthat can be systemically administered.

[0038] A water soluble drug is one that has a solubility of greater than1.0 mg/mL in water at body temperature.

[0039] The term “matrix” or “biocompatible matrix” are usedinterchangeably to refer to a medium or material that, upon implantationin a subject, does not elicit a detrimental response sufficient toresult in the rejection of the matrix. The matrix typically does notprovide any therapeutic responses itself, though the matrix may containor surround a therapeutic agent, and/or modulate the release of thetherapeutic agent into the body. A matrix is also a medium that maysimply provide support, structural integrity or structural barriers. Thematrix may be polymeric, non-polymeric, hydrophobic, hydrophilic,lipophilic, amphiphilic, and the like.

[0040] The term “bioresorbable” refers to a matrix, as defined herein,that can be broken down by either chemical or physical process, uponinteraction with a physiological environment. The matrix can erode ordissolve. A bioresorbable matrix serves a temporary function in thebody, such as drug delivery, and is then degraded or broken intocomponents that are metabolizable or excretable, over a period of timefrom minutes to years, preferably less than one year, while maintainingany requisite structural integrity in that same time period.

[0041] The term “pharmaceutically acceptable” refers to a matrix or anadditive, as defined herein, that is not toxic to the host or patient.When in reference to a matrix, it provides the appropriate storageand/or delivery of therapeutic, activating or deactivating agents, asdefined herein, and does not interfere with the effectiveness or thebiological activity of the agent.

[0042] The term “mixing layer” refers to a matrix layer which isadjacent a therapeutic agent layer. Before the mixing layer isintroduced to the device, the mixing layer preferably contains notherapeutic agent, or it contains a therapeutic agent which is differentfrom the therapeutic agent of the therapeutic agent layer. The mixinglayer is introduced in a liquified state and may mix with thetherapeutic agent layer causing the mixing layer to incorporate aportion of the adjacent therapeutic agent layer once the layer has atleast partially solidified. The mixing layer may also serve to controlthe rate at which a drug is released into the reaction environment. Therelease rate can be controlled by the rate of erosion or dissolution ofthe mixing layer or by the rate of diffusion of the therapeutic agentfrom within the mixing and therapeutic agent layers. The mixing layer ispreferably bioresorbable.

[0043] The term “erosion” refers to the process by which the componentsof a medium or matrix are bioresorbed and/or degraded and/or broken downby either chemical or physical processes. For example in reference topolymers, erosion can occur by cleavage or hydrolysis of the polymerchains, such that the molecular weight of the polymer is lowered. Thepolymer of lower molecular weight will have greater solubility in waterand is therefore dissolved away. In another example, erosion occurs byphysically breaking apart upon interaction with a physiologicalenvironment.

[0044] The term “erosion rate” is a measure of the amount of time ittakes for the erosion process to occur and is usually report in unitarea per unit time.

[0045] The term “degrade” or “deactivate” refers to any process thatcauses an active component, such as a therapeutic agent, to becomeunable, or less able, to perform the action which it was intended toperform when incorporated in the device.

[0046] The term “polymer” refers to molecules formed from the chemicalunion of two or more repeating units, called monomers. Accordingly,included within the term “polymer” may be, for example, dimers, trimersand oligomers. The polymer may be synthetic, naturally-occurring orsemisynthetic. In preferred form, the term “polymer” refers to moleculeswhich typically have a M_(w) greater than about 3000 and preferablygreater than about 10,000 and a M_(w) that is less than about 10million, preferably less than about a million and more preferably lessthan about 200,000. Examples of polymers include but are not limited to,poly-α-hydroxy acid esters such as, polylactic acid, polyglycolic acid,polylactic-co-glycolic acid, polylactic acid-co-caprolactone;polyethylene glycol and polyethylene oxide, polyvinyl pyrrolidone,polyorthoesters; polysaccharides and polysaccharide derivatives such aspolyhyaluronic acid, polyalginic acid, chitin, chitosan, chitosanderivatives, cellulose, hydroxyethylcellulose, hydroxypropylcellulose,carboxymethylcellulose; polypeptides, and proteins such as polylysine,polyglutamic acid, albumin; polyanhydrides; polyhydroxy alkonoates suchas polyhydroxy valerate, polyhydroxy butyrate, and the like.

[0047] The term “lipid”, as used herein, refers to a matrix thatcomprises preferably non-polymeric small organic, synthetic ornaturally-occurring, compounds which are generally amphipathic andbiocompatible. The lipids typically comprise a hydrophilic component anda hydrophobic component. Exemplary lipids include, for example, fattyacids, fatty acid esters, neutral fats, phospholipids, glycolipids,aliphatic alcohols, waxes, terpenes, steroids and surfactants. Termlipid is also meant to include derivatives of lipids. More specificallythe term lipids includes but is not limited to phosphatidylcholine,phosphatidylethanolamine, phosphatidylserine, sphingomyelin as well assynthetic phospholipids such as dimyristoyl phosphatidylcholine,dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine,distearoyl phosphatidylglycerol, dipalmitoyl phosphatidyl-glycerol,dimyristoyl phosphatidylserine, distearoyl phosphatidylserine anddipalmitoyl phosphatidylserine.

[0048] The term “additives” refers to pharmaceutically acceptablecompounds, materials, and compositions that may be included in a matrixalong with a therapeutic agent. An additive may be encapsulated in or onor around a matrix. It may be homogeneously or heterogeneously disposed,as defined herein, in the matrix. Some examples of additives arepharmaceutically acceptable excipients, adjuvants, carriers,antioxidants, preservatives, buffers, antacids, and the like, such asthose disclosed in Remington: The Science and Practice of Pharmacy,Gennaro, ed., Mack Publishing Co., Easton, Pa., 19th ed., 1995.

[0049] The term “holes” refers to holes of any shape and includes boththrough-openings and recesses.

[0050] The term “reaction environment” or “environment” refers to thearea between a tissue surface abutting the device and the first intactlayer of beneficial agent within a hole in the medical device.

[0051] The term “liquified” is used herein to define a component whichis put in a liquid state either by heating the component to atemperature higher than its melting point, or glass transitiontemperature, or by dissolving the component in a solvent. The typicalliquified materials of the present invention will have a viscosity ofless than about 13,000 centipoise, and preferably less about 10,000centipoise.

[0052] The term “homogeneously disposed” or “homogeneously dispersed”refers to a mixture in which each of the components are uniformlydispersed within the matrix.

[0053] The term “heterogeneously disposed” or “heterogeneouslydispersed” refers to a mixture in which the components are not mixeduniformly into a matrix.

[0054] The term “solid solution” refers to a homogeneously dispersedmixture of two or more substances. A component that is mixed uniformlyin a matrix in such a manner that the component is macroscopicallyindistinguishable from the matrix itself. An example of a solid solutionis a metal alloy, such as brass.

[0055] The term “multi-phase mixture” refers to a mixture of two or moresubstances in which at least one component is macroscopicallydistinguishable from the matrix itself. An example of a multi-phasemixture is a macro emulsion.

[0056] Implantable Medical Devices with Holes

[0057]FIG. 1 illustrates a medical device 10 according to the presentinvention in the form of a stent design with large, non-deforming struts12 and links 14, which can contain holes 20 without compromising themechanical properties of the struts or links, or the device as a whole.The non-deforming struts 12 and links 14 may be achieved by the use ofductile hinges 16 which are described in detail in U.S. Pat. No.6,241,762 which is incorporated hereby by reference in its entirety. Theholes 20 serve as large, protected reservoirs for delivering variousbeneficial agents to the device implantation site.

[0058] The relatively large, protected openings 20, as described above,make the expandable medical device of the present invention particularlysuitable for delivering larger molecules or genetic or cellular agents,such as, for example, protein drugs, enzymes, antibodies, antisenseoligonucleotides, ribozymes, gene/vector constructs, and cells(including but not limited to cultures of a patient's own endothelialcells). Many of these types of agents are biodegradable or fragile, havea very short or no shelf life, must be prepared at the time of use, orcannot be pre-loaded into delivery devices such as stents during themanufacture thereof for some other reason. The large holes 20 in theexpandable device of the present invention form protected areas orreceptors to facilitate the loading of such an agent either at the timeof use or prior to use, and to protect the agent from abrasion andextrusion during delivery and implantation.

[0059] The volume of beneficial agent that can be delivered using holes20 is about 3 to 10 times greater than the volume of a 5 micron coatingcovering a stent with the same stent/vessel wall coverage ratio. Thismuch larger beneficial agent capacity provides several advantages. Thelarger capacity can be used to deliver multi-drug combinations, eachwith independent release profiles, for improved efficacy. Also, largercapacity can be used to provide larger quantities of less aggressivedrugs and to achieve clinical efficacy without the undesirableside-effects of more potent drugs, such as retarded healing of theendothelial layer.

[0060] Holes also decrease the surface area of the beneficial agentbearing compounds to which the vessel wall surface is exposed. Fortypical devices with beneficial agent openings, this exposure decreasesby a factors ranging from about 6:1 to 8:1, by comparison with surfacecoated stents. This dramatically reduces the exposure of vessel walltissue to polymer carriers and other agents that can cause inflammation,while simultaneously increasing the quantity of beneficial agentdelivered, and improving control of release kinetics.

[0061]FIG. 2 shows a cross section of a medical device 10 in which oneor more beneficial agents have been loaded into the opening 20 indiscrete layers 30. Examples of some methods of creating such layers andarrangements of layers are described in U.S. patent application No.09/948,989, filed on Sep. 7, 2001, which is incorporated herein byreference in its entirety.

[0062] According to one example, the total depth of the opening 20 isabout 125 to about 140 microns, and the typical layer thickness would beabout 2 to about 50 microns, preferably about 12 microns. Each typicallayer is thus individually about twice as thick as the typical coatingapplied to surface-coated stents. There would be at least two andpreferably about ten to twelve such layers in a typical opening, with atotal beneficial agent thickness about 4 to 28 times greater than atypical surface coating. According to one preferred embodiment of thepresent invention, the openings have an area of at least 5×10⁻⁶ squareinches, and preferably at least 7×10⁻⁶ square inches.

[0063] Since each layer is created independently, individual chemicalcompositions and pharmacokinetic properties can be imparted to eachlayer. Numerous useful arrangements of such layers can be formed, someof which will be described below. Each of the layers may include one ormore agents in the same or different proportions from layer to layer.The layers may be solid, porous, or filled with other drugs orexcipients.

[0064]FIG. 2 shows an arrangement of layers provided in a throughopening 20 which include a barrier layer 30, one or more therapeuticagent layers 40, and a plurality of mixing layers 50. The barrier layer30 substantially prevents delivery of the therapeutic agent in thetherapeutic agent layers and the mixing layers from being delivered to aside of the device 10 adjacent the barrier layer. The therapeutic agentlayer 40 and the mixing layers 50 are loaded sequentially into themedical device opening 20, such that a concentration gradient oftherapeutic agent is present with a highest concentration of therapeuticagent at the interior layers closer to the barrier layer and a lowestconcentration of therapeutic agent at the exterior mixing layers. Thecombination of therapeutic agent layer and mixing agent layers allows awater soluble therapeutic agent to be delivered over an extended timeperiod of time. The time period for delivery can be modulated fromminutes, to hours, to days. Preferably the time period for delivery isgreater than 1 day, more preferably greater than 3 days.

[0065] In one embodiment the layers are loaded into the medical deviceby first loading the therapeutic agent layer, 40, into the holes of themedical device in a liquefied state. The therapeutic agent layer is thenallowed to solidify. A first mixing layer, 50, is then loaded into theholes within the medical device in a liquefied state. When the liquidmixing layer, 50, comes into contact with the therapeutic agent layer,40, a portion of the therapeutic agent layer is liquefied allowing aco-mingling of some of the components of each of the two layers. Whenthe mixing layer solidifies, there is therapeutic agent within themixing layer.

[0066] Optionally, a second mixing layer is then loaded into the holeswithin the medical device in a liquefied state. When the second liquidmixing layer comes into contact with the first mixing layer, a portionof the first mixing layer is liquefied allowing a co-mingling of some ofthe components of each of the two layers. When the mixing layersolidifies, there is an amount of therapeutic agent within the secondmixing layer that is less than the amount of therapeutic agent in thefirst mixing layer. Subsequent additions of mixing layers results in theformation of multiple mixing layers with decreasing amounts oftherapeutic agent. The gradient of therapeutic agent incorporated in amixing layers adjacent the therapeutic agent layer is especiallyadvantageous for the delivery of water soluble drugs such as a2-chlorodeoxyadenosine.

[0067] An example of a binding agent is Poly vinylpyrrolidone. Thepolymers of the therapeutic agent layer may be the same as or differentfrom the polymer of the mixing layers. The polymer can be liquefied bymaintaining the material at a temperature that is greater than itsmelting point, or glass transition temperature, or by dissolution in asolvent.

[0068] Some examples of hydrophobic, bioresorbable matrix materials forthe mixing layer are lipids, fatty acid esters, such as glycerides. Theerosion rate is controlled by varying the hydrophilic-lipophilic balance(HLB). The polymers of the individual mixing layers may be the same ordifferent. These polymers can be liquefied by maintaining the materialat a temperature that is greater than its melting point, or glasstransition temperature, or by dissolution in a solvent.

[0069] Bioerosion of the mixing layers may induce the release of thetherapeutic agent from either the mixing layer or the therapeutic agentlayer. However, in some embodiments, the mixing layer remainsessentially intact, and the therapeutic agent is released into thereaction environment by diffusing from the therapeutic agent layer andthrough the mixing layers.

[0070] Therapeutic Layer Formulations

[0071] The therapeutic agent layers of the present invention may consistof the therapeutic agent alone or a therapeutic agent in combinationwith a bioresorbable matrix. The matrix of the therapeutic agent layerscan be made from pharmaceutically acceptable polymers, such as thosetypically used in medical devices. This polymer may also be referred toas a binding agent. Typically, when a lesser amount of matrix materialis used relative to the amount of drug, for example 5-50% polymer to95-50% drug, the material is called a binding agent.

[0072] Polymers useful in the therapeutic agent layer as either a matrixmaterial or a binding agent are well known and include but are notlimited to poly-α-hydroxy acid esters such as, polylactic acid,polyglycolic acid, polylactic-co-glycolic acid, polylacticacid-co-caprolactone; polyethylene glycol and polyethylene oxide; polyvinyl alcohol, polyvinyl pyrrolidone; polyorthoesters; polysaccharidesand polysaccharide derivatives such as polyhyaluronic acid, aglycosaminoglycan, polyalginic acid, chitin, chitosan, chitosanderivatives, cellulose, hydroxyethylcellulose, hydroxypropylcellulose,carboxymethylcellulose; polypeptides, and proteins such as polylysine,polyglutamic acid, albumin; polyanhydrides; polyhydroxy alkonoates suchas polyhydroxy valerate, polyhydroxy butyrate, and the like, andcopolymers thereof. Particularly useful polymers include poly ethyleneglycol, poly ethylene oxide, poly vinylpyrrolidone, poly vinyl alcohol,polysaccharides and their derivatives, poly hyaluronic acid, polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, poly peptides, poly lysine, poly glutamic acid, and proteins.These polymers and copolymers can be prepared by methods well known inthe art (see, for example, Rempp and Merril: Polymer Synthesis, 1998,John Wiley and Sons) in or can be used as purchased from Alkermes, inCambridge, Mass. or Birmingham Polymer Inc., in Birmingham, Ala.

[0073] The preferred polymer for use in the therapeutic layer of thepresent invention is poly vinylpyrrolidone (PVP). The rate at which thepolymer resorbs is determined by the selection of the subsequentlyloaded mixing layers.

[0074] Therapeutic Agent Formulations

[0075] Some drugs that are useful in the present invention are lowmolecular weight synthetic oligonucleotides and polypeptides, such as2-chlorodeoxyadenosine, restinase, or restin NG.

[0076] Typical formulations for therapeutic agents incorporated in thesemedical devices are well known to those skilled in the art and includebut are not limited to solid particle dispersions, encapsulated agentdispersions, and emulsions, suspensions, liposomes or microparticles,wherein said liposome or microparticle comprise a homogeneous orheterogeneous mixture of the therapeutic agent.

[0077] The amount of the drug that is present in the device, and that isrequired to achieve a therapeutic effect, depends on many factors, suchas the minimum necessary dosage of the particular drug, the condition tobe treated, the chosen location of the inserted device, the actualcompound administered, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

[0078] The appropriate dosage level of the therapeutic agent, for moretraditional routes of administration, are known to one skilled in theart. These conventional dosage levels correspond to the upper range ofdosage levels for compositions, including a physiologically activesubstance and traditional penetration enhancer. However, because thedelivery of the active substance occurs at the site where the drug isrequired, dosage levels significantly lower than a conventional dosagelevel may be used with success. Ultimately, the percentage oftherapeutic agent in the composition is determined by the requiredeffective dosage, the therapeutic activity of the particularformulation, and the desired release profile. In general, the activesubstance will be present in the composition in an amount from about0.0001% to about 99%, more preferably about 0.01% to about 80% by weightof the total composition depending upon the particular substanceemployed. However, generally the amount will range from about 0.05% toabout 75% by weight of the total composition.

[0079] Mixing Layer Formulations

[0080] The mixing layers of the present invention are comprised of abioresorbable or bioresorbable matrix and optionally contain additionaladditives, therapeutic agents, activating agents, deactivating agents,and the like as described in U.S. patent application Ser. No.10/253,020. In addition to the polymer materials described above, themixing layer may also be comprised of pharmaceutically acceptable lipidsor lipid derivatives, which are well known in the art and include butare not limited to fatty acids, fatty acid esters, lysolipids,phosphocholines, (Avanti Polar Lipids, Alabaster, Ala.), including1-alkyl-2-acetoyl-sn-glycero 3-phosphocholines, and1-alkyl-2-hydroxy-sn-glycero 3-phosphocholines; phosphatidylcholine withboth saturated and unsaturated lipids, includingdioleoylphosphatidylcholine; dimyristoyl-phosphatidylcholine;dipentadecanoylphosphatidylcholine; dilauroylphosphatidyl-choline;dipalmitoylphosphatidylcholine (DPPC); distearoylphosphatidylcholine(DSPC); and diarachidonylphosphatidylcholine (DAPC);phosphatidyl-ethanolamines, such as dioleoylphosphatidylethanolamine,dipahnitoyl-phosphatidylethanolamine (DPPE) anddistearoylphosphatidylefhanolamine (DSPE); phosphatidylserine;phosphatidylglycerols, including distearoylphosphatidylglycerol (DSPG);phosphatidylinositol; sphingolipids such as sphingomyelin; glucolipids;sulfatides; glycosphingolipids; phosphatidic acids, such asdipahmitoylphosphatidic acid (DPPA) and distearoylphosphatidic acid(DSPA); palmitic acid; stearic acid; arachidonic acid; oleic acid;lipids bearing polymers, such as chitin, hyaluronic acid,polyvinylpyrrolidone or polyethylene glycol (PEG), also referred toherein as “pegylated lipids”, with preferred lipids bearing polymersincluding DPPE-PEG (DPPE-PEG), which refers to the lipid DPPE having aPEG polymer attached thereto, including, for example, DPPE-PEG5000,which refers to DPPE having attached thereto a PEG polymer having a meanaverage molecular weight of about 5000; lipids bearing sulfonated mono-,di-, oligo- or polysaccharides; cholesterol, cholesterol sulfate andcholesterol hemisuccinate; tocopherol hemisuccinate; lipids with etherand ester-linked fatty acids; polymerized lipids (a wide variety ofwhich are well known in the art); diacetyl phosphate; dicetyl phosphate;stearylamine; cardiolipin; phospholipids with short chain fatty acids ofabout 6 to about 8 carbons in length; synthetic phospholipids withasymmetric acyl chains, such as, for example, one acyl chain of about 6carbons and another acyl chain of about 12 carbons; ceramides; non-ionicliposomes including niosomes such as polyoxyethylene fatty acid esters,polyoxyethylene fatty alcohols, polyoxyethylene fatty alcohol ethers,polyoxyethylated sorbitan fatty acid esters, glycerol polyethyleneglycol oxystearate, glycerol polyethylene glycol ricinoleate,ethoxylated soybean sterols, ethoxylated castor oil,polyoxyethylene-polyoxypropylene polymers, and polyoxyethylene fattyacid stearates; sterol aliphatic acid esters including cholesterolsulfate, cholesterol butyrate, cholesterol iso-butyrate, cholesterolpalmitate, cholesterol stearate, lanosterol acetate, ergosterolpalmitate, and phytosterol n-butyrate; sterol esters of sugar acidsincluding cholesterol glucuronide, lanosterol glucuronide,7-dehydrocholesterol glucuronide, ergosterol glucuronide, cholesterolgluconate, lanosterol gluconate, and ergosterol gluconate; esters ofsugar acids and alcohols including lauryl glucuronide, stearoylglucuronide, myristoyl glucuronide, lauryl gluconate, myristoylgluconate, and stearoyl gluconate; esters of sugars and aliphatic acidsincluding sucrose diacetate hexaisobutyrate (SAIB), sucrose laurate,fructose laurate, sucrose palritate, sucrose stearate, glucuronic acid,gluconic acid and polyuronic acid; saponins including sarsasapogenin,smilagenin, hederagenin, oleanolic acid, and digitoxigenin; glyceroldilaurate, glycerol trilaurate, glycerol monolaurate, glyceroldipalmitate, glycerol and glycerol esters including glyceroltripalmitate, glycerol monopalmitate, glycerol distearate, glyceroltristearate, glycerol monostearate, glycerol monomyristate, glyceroldimyristate, glycerol trimyristate; long chain alcohols includingn-decyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, andn-octadecyl alcohol; 1,2-dioleoyl-sn-glycerol;1,2-dipalmitoyl-sn-3-succinylglycerol;1,3-dipalmitoyl-2-succinylglycerol;1-hexadecyl-2-palmitoylglycerophosphoethanolamine andpalmitoylhomocysteine, and/or combinations thereof.

[0081] If desired, a cationic lipid may be used, such as, for example,N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA),1,2-dioleoyloxy-3-(trimethylammonio)propane (DOTAP); and1,2-dioleoyl-3-(4′-trimethylammonio)butanoyl-sn-glycerol (DOTB). If acationic lipid is employed in the lipid compositions, the molar ratio ofcationic lipid to non-cationic lipid may be, for example, from about1:1000 to about 1:100. Preferably, the molar ratio of cationic lipid tonon-cationic lipid may be from about 1:2 to about 1:10, with a ratio offrom about 1:1 to about 1:2.5 being preferred. Even more preferably, themolar ratio of cationic lipid to non-cationic lipid may be about 1:1.

[0082] These lipid materials are well known in the art and can be usedas purchased from Avanti, Burnaby, B.C. Canada.

[0083] The preferred lipids for use in the present invention arephosphatidyl-choline, phosphatidylethanolamine, phosphatidylserine,sphingomyelin as well as synthetic phospholipids such as dimyristoylphosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoylphosphatidylcholine, distearoyl phosphatidyl-glycerol, dipalmitoylphosphatidylglycerol, dimyristoyl phosphatidylserine, distearoylphosphatidylserine and dipalmitoyl phosphatidylserine.

[0084] The rate at which the bioresorbable matrix resorbs is determinedby the choice of lipid, the molecular weight, and the ratio of thechosen materials.

[0085] The mixing layer can resorb by either chemical mechanisms such aschemical interactions, dissolution in water, hydrolysis, or reactionwith enzymes, or by physical erosion mechanisms.

[0086] Composite Matrix of Therapeutic Agent and Mixing Layers

[0087] Because of the methods used to make the implantable devices ofthe present invention, the therapeutic agent that is first incorporatedin the therapeutic agent layer is ultimately found throughout thetherapeutic agent layer and the mixing layers. Each layer is introducedinto the holes of the device while in a liquified state and then isallowed to solidify. A layer previously solidified within the wells ispartially liquefied again when a new liquified layer is introduced ontop of the existing solid layer. This allows for the materials of thesetwo layers to mix. The concentration of a therapeutic agent in a laterapplied layer is going to be smaller than the concentration oftherapeutic agent in the previously formed layers. This layer methodallows for a concentration gradient of therapeutic agent to be formed inthe layers within the medical device.

[0088] The mixing layer and the therapeutic agent layer, into which thetherapeutic agent is homogeneously or heterogeneously dispersed, mayeach be a homogeneous or heterogeneous mixture. For example, if thepolymers of the mixing layer and the polymers of the therapeutic agentlayer are mutually miscible, then the material contained within theholes of the implantable medical device will be a solid solution, or aone phase mixture, comprising each of these polymers. Examples ofpolymer systems that can form a one phase homogeneous mixture includebut are not limited to 1) polyvinyl pyrrolidone and poly vinyl alcohol,2) polyvinyl pyrrolidone and polyethylene glycol, 3) polyvinylpyrrolidone and polyalginate, and 4) polyvinyl pyrrolidone andcarboxymethylcellulose.

[0089] If the polymers comprising the mixing layer and therapeutic agentlayer are only slightly miscible or are immiscible, then the materialcontained within the holes of the implantable medical device will be atwo phase (or phase separated) mixture comprising each of thesepolymers. The two phase mixture may be

[0090] i) phase domains of the mixing layer polymer dispersed in acontinuous phase of the therapeutic agent layer polymer;

[0091] ii) phase domains of the therapeutic agent layer polymerdispersed in a continuous phase of the mixing layer polymer; or

[0092] iii) two co-continuous phases each of the mixing layer polymerand the therapeutic agent layer polymer.

[0093] The type of two-phase mixture is determined by judicious choiceof polymer for each layer, and the percentage of each polymer thatdissolves in the solvent used to introduce the mixing layer(s). Examplesof polymer systems that can form a multi-phase homogeneous mixtureinclude but are not limited to 1) 50% by volume of polylactide and 50%by volume of poly vinylpyrrolidone 2) Poly(lactide-co-glycolide) andpolyethylene oxide, and 3) poly DL-lactide and polyethylene oxide.

[0094] Additionally, two phase mixtures can be prepared such that onephase is a homogeneous mixture of a first weight ratio of mixing layerpolymer and therapeutic agent layer polymer and a second phase is a is ahomogeneous mixture of a second weight ratio of the same mixing layerpolymer and therapeutic agent layer polymer. Generally, to achieve phaseseparation and a resulting two phase mixture, one phase will consistlargely of mixing layer polymer and a second phase will consist largelyof therapeutic agent layer polymer.

[0095] The therapeutic agent maybe homogeneously or heterogeneouslydisposed within the homogeneous or heterogeneous matrix formed by thepolymers of the mixing layer and the therapeutic agent layer. Forexample, if the therapeutic agent is fully soluble in each of the mixinglayer and therapeutic agent layer polymers, then the distribution of thetherapeutic agent will be controlled by the relative solubility of theagent in each polymer and the relative miscibility of the polymers ineach other as well as their respective volume proportions. If thedesired amount of therapeutic agent exceeds the solubility in either orboth of the mixing layer or the therapeutic agent layer, then thetherapeutic agent can theoretically be found in four separate phaseswithin the final composite matrix.

[0096] 1) homogeneously dissolved in the mixing layer polymer;

[0097] 2) dispersed as a second phase within the mixing layer polymer;

[0098] 3) homogeneously dissolved in the therapeutic agent layer polymerwhich is itself in a continuous or non-continuous phase with respect tothe therapeutic agent layer; or

[0099] 4) dispersed as a second phase within the therapeutic agent layerpolymer.

[0100] The distribution of the therapeutic agent, and thus the kineticrelease profile, may be controlled by the selection of the molecularweight of the polymer, the solubility of the polymer and the volumepercentage of each of the polymers used within the mixing and thetherapeutic agent layers.

[0101] Any of the specific polymers or chemicals listed as a usefulmatrix material for the mixing layer may also be used in the therapeuticagent layer as a binder and vise-versa. Generally, the material chosenas a binding agent in therapeutic agent layer has different physicalproperties than the material used as the matrix in the mixing layers.This may be accomplished by using two different chemicals or polymers.Alternatively, the same type of polymer maybe used as long as thephysical properties, such as solubility, or hydrophobicity,hydrophilicity or melting point or glass transition temperature can bealtered by changing the polymers molecular weight or by addingadditional components or additives, such as co-polymers, elasticizers,plasticizers and the like.

[0102] The therapeutic agent, which can be heterogeneously orhomogeneously dispersed in the therapeutic agent layer and/or the mixinglayer, can be a drug, or a drug formulated into a microcapsule, niosome,liposome, microbubble, microsphere, or the like. In addition, the mixinglayer may contain more than one therapeutic agent. For example, a watersensitive drugs, such as a limus, or any other drug that must beadministered through intravenous, intramuscular, or subcutaneously,could be incorporated in a hydrophobic matrix such as SAIB, or fattyacid ester.

[0103] Bioresorbable polymers may also be used to form barrier layersthat resorb at a rate that can be predetermined base on the compositionand that contain no therapeutic agent.

[0104] In one embodiment, the mixing layers, 50, of the presentinvention are essentially hydrophobic and are bioresorbed at a rate thatcan be selected based on the polymers that are chosen in theformulation. The therapeutic agent layer, 40, is comprised of about 50%to about 60% of a therapeutic agent and about 40% to about 50% of apharmaceutically acceptable bioresorbable polymer that acts primarily asa binding agent.

[0105] Uses for Implantable Medical Devices

[0106] Although the present invention has been describe with referenceto a medical device in the form of a stent, the medical devices of thepresent invention can also be medical devices of other shapes useful forsite-specific and time-release delivery of drugs to the body and otherorgans and tissues. The drugs may be delivered to the vasculatureincluding the coronary and peripheral vessels for a variety oftherapies, and to other lumens in the body including the esophagus,urethera, and the bile duct. The drugs may increase lumen diameter,create occlusions, or deliver the drug for other reasons.

[0107] Medical devices and stents, as described herein, are useful forthe prevention of amelioration of restenosis, particularly afterpercutaneous transluminal coronary angioplasty and intraluminal stentplacement. In addition to the timed or sustained release ofanti-restenosis agents, other agents such as anti-inflammatory agentsmay be incorporated in to the multi-layers incorporated in the pluralityof holes within the device. This allows for site-specific treatment orprevention any complications routinely associated with stent placementthat are known to occur at very specific times after the placementoccurs.

[0108] The methods for loading beneficial agents into openings in anexpandable medical device may include known techniques such as dippingand coating and also known piezoelectric micro-jetting techniques.Micro-injection devices may be used to deliver precise amounts of one ormore liquid beneficial agents including mixing layers, therapeutic agentlayers, and any other layers to precise locations on the expandablemedical device in a known manner. The beneficial agents may also beloaded by manual injection devices.

EXAMPLES

[0109] In the examples below, the following abbreviations have thefollowing meanings. If an abbreviation is not defined, it has itsgenerally accepted meaning.

[0110] mL=milliliters

[0111] M=Molar

[0112] wt.=weight

[0113] vol.=volume

[0114] μL=microliters

[0115] μm=micrometers

[0116] nm=nanometers

[0117] DMSO=Dimethyl sulfoxide

[0118] NMP=N-methylpyrrolidone

[0119] DMAC=Dimethyl acetamide

Example 1 Formulation Comprising a Gradient of a Therapeutic Agentwithin the Mixing Layers

[0120] A first mixture of poly(lactide-co-glycolide) (PLGA) (BirminghamPolymers, Inc), lactide:glycolide::85:15, (M_(v)>100,000 Daltons) 7% wt.and a suitable organic solvent, such as DMSO, NMP, or DMAC 93% wt. isprepared. The mixture is loaded dropwise into holes in the stent, thenthe solvent is evaporated to begin formation of the barrier layer. Asecond barrier layer is laid over the first by the same method offilling polymer solution into the hole followed by solvent evaporation.The process is continued until five individual layers have been laiddown to form the barrier layer.

[0121] A second mixture of 2-chlorodeoxyadenosine, 50% solids basis, andpoly vinylpyrrolidone (PVP), 50% solids basis, in a suitable organicsolvent, such as DMSO, is introduced into holes in the stent over thebarrier layer. The solvent is evaporated to form a drug filledtherapeutic agent layer. The filling and evaporation procedure isrepeated until the hole is filled to about 50% of its total volume withdrug in therapeutic agent layer layered on top of the barrier layer.

[0122] Three layers of a third solution, of poly(lactide-co-glycolide)(PLGA), lactide:glycolide::50:50, (M_(v)≅80,000 Daltons) 8% wt. and asuitable organic solvent, such as DMSO, are then laid down over thetherapeutic agent layer to form three mixing layers. When each of themixing layers is loaded into the stent, a portion of the layer beneathis incorporated in the new layer. In this way multiple mixing layers areformed containing a concentration gradient of therapeutic agent.

[0123] Following implantation of the filled stent in vivo, the2-chlorodeoxyadenosine contained within the stent is delivered slowlyover a time period of about 1 to about 8 days. The barrier layerprevents the therapeutic agent from being delivered out the barrierlayer side of holes in the stent.

Example 2 Measurement of Paclitaxel Release Rates from a Medical Devicewith Multiple Therapeutic Agent Layers

[0124] A solution of phosphate buffered saline (PBS) is prepared bydissolving five “Phosphate Buffered Saline Tablets” (Sigma-Aldrich Co.,catalog #P-4417) in 1000 mL deionized water to provide a solution with apH of 7.4, 0.01 M in phosphate buffer, 0.0027 M in potassium chlorideand 0.137 M in sodium chloride. This PBS solution is used as a ReleaseSolution.

[0125] The elution rate of drug from the multilayered stent of Example 1is determined in a standard sink condition experiment.

[0126] A first 10 mL screw capped vial is charged with release solution,3 mL, then placed in a shaking water bath held at 37° C. untiltemperature has equilibrated. The above stent containing a concentrationgradient of drug in the mixing layers is placed into the releasesolution, shaking at 60 cycles per minute commenced, and the stent isheld immersed in the release solution for a period of time. The stent isthen placed in a second screw capped vial is charged with releasesolution, 3 mL, at 37° C., and held for a period of time. The firstrelease solution is called sample #1. From time to time, the stent isremoved from release solution in one vial and placed into fresh solutionin the next vial to generate a series of samples containing varyingamounts of drug eluted from the stent.

[0127] The amount of drug in a given release solution sample isdetermined by High Pressure Liquid Chromatography (HPLC). The followingconditions are used:

[0128] Analysis Column: Sym. C₁₈ (5μm, 3.9×150 mm, Waters Corp., Mass.)

[0129] Mobile phase: Water/Acetonitrile :: 55% vol./45% vol.

[0130] Flow Rate: 1 mL/minute

[0131] Temperature: 25° C.

[0132] Detection wavelength: 227 nm

[0133] Injection volume: 50μL

[0134] Retention time: 10.5 minutes

[0135] By comparison with a calibration curve generated from known stocksolutions, the amount of drug eluted into the release solution duringany time period of the experiment can be calculated.

[0136] Methods and results for measuring release profiles are publishedin A. Finkelstein et al., “The Conor Medsystems Stent: A programmableDrug Delivery Device,” TCT 2001 Conference, Washington, D.C., September2001.

[0137] While the invention has been described in detail with referenceto the preferred embodiments thereof, it will be apparent to one skilledin the art that various changes and modifications can be made andequivalents employed, without departing from the present invention.

What is claimed is:
 1. An implantable medical device comprising: animplantable device body having a plurality of holes; a therapeutic agentprovided in a first therapeutic agent layer and contained within theplurality of holes in the device body; and at least one mixing layerprovided adjacent the first therapeutic agent layer in the plurality ofholes; wherein the therapeutic agent layer and the at least one mixinglayer together contain a concentration gradient of said therapeuticagent and allow for the controlled release of the therapeutic agentcontained within the therapeutic agent layer and the at least one mixinglayer.
 2. The implantable medical device of claim 1, wherein the atleast one mixing layer is a pharmaceutically acceptable bioresorbablematrix that allows the therapeutic agent contained within thetherapeutic agent layer and the at least one mixing layer to be releasedas the matrix resorbs.
 3. The implantable medical device of claim 2,wherein said pharmaceutically acceptable bioresorbable matrix comprisesat least one pharmaceutically acceptable polymer.
 4. The implantablemedical device of claim 3, wherein said pharmaceutically acceptablepolymer is selected from the group consisting of polylactic acid,polyglycolic acid, polylactic-co-glycolic acid, polylacticacid-co-caprolactone, polyethylene glycol, polyethylene oxide, polylactic acid-block-poly ethylene glycol, poly glycolic acid-block-polyethylene glycol, poly lactide-co-glycolide-block-poly ethylene glycol,poly ethylene glycol-block-lipid, polyvinyl pyrrolidone, poly vinylalcohol, a glycosaminoglycan, polyorthoesters, polysaccharides,polysaccharide derivatives, polyhyaluronic acid, polyalginic acid,chitin, chitosan, chitosan derivatives, cellulose,hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose,polypeptides, polylysine, polyglutamic acid, albumin, polyanhydrides,polyhydroxy alkonoates, polyhydroxy valerate, polyhydroxy butyrate,proteins, polyphosphate esters, lipids, and mixtures thereof.
 5. Theimplantable medical device of claim 1, wherein the therapeutic agentlayer comprises the therapeutic agent and a water soluble binding agent.6. The implantable medical device of claim 5, wherein the binding agentis a pharmaceutically acceptable polymer selected from the groupconsisting of poly ethylene glycol, poly ethylene oxide, polyvinylpyrrolidone, poly vinyl alcohol, a glycosaminoglycan,polysaccharides, polysaccharide derivatives, poly hyaluronic acid, polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, poly peptides, poly lysine, poly glutamic acid, and proteins.7. The implantable medical device of claim 5, wherein the at least onemixing layer includes a polymer different from the water soluble bindingagent
 8. The implantable medical device of claim 7, wherein the at leastone mixing layer includes a plurality of mixing layers formed bysequential delivery of a substantially identical composition to theimplantable medical device for each of the layers which take on theconcentration gradient in the plurality of holes.
 9. The implantablemedical device of claim 1, wherein the at least one mixing layer isformed by delivery of a polymer without the therapeutic agent to theholes and further wherein the mixing layer acquires the therapeuticagent by liquefying a portion of the therapeutic agent layer.
 10. Theimplantable medical device of claim 5, wherein said therapeutic agent ishomogeneously dispersed as a solid solution in said therapeutic agentlayer.
 11. The implantable medical device of claim 5, wherein saidtherapeutic agent is homogeneously dispersed as multi-phase mixture insaid therapeutic agent layer.
 12. The implantable medical device ofclaim 5, wherein said therapeutic agent is heterogeneously disposed insaid therapeutic agent layer.
 13. The implantable medical device ofclaim 5, wherein said therapeutic agent is homogeneously orheterogeneously disposed in said therapeutic agent layer as a solidparticle dispersion, encapsulated agent dispersion, an emulsion, asuspension, a liposome, niosome, or a microparticle, wherein saidniosome, liposome or microparticle comprise a homogeneous orheterogeneous mixture of the therapeutic agent.
 14. The implantablemedical device of claim 4, wherein said therapeutic agent from thetherapeutic agent layer is homogeneously dispersed as a solid solutionin said at least one mixing layer.
 15. The implantable medical device ofclaim 4, wherein said therapeutic agent is homogeneously dispersed asmulti-phase mixture in said at least one mixing layer.
 16. Theimplantable medical device of claim 4, wherein said therapeutic agentfrom the therapeutic agent layer is heterogeneously disposed in said atleast one mixing layer.
 17. The implantable medical device of claim 16,wherein said therapeutic agent from the therapeutic agent layer ishomogeneously or heterogeneously disposed in said at least one mixinglayer as a solid particle dispersion, encapsulated agent dispersion, anemulsion, a suspension, a liposome, niosome, or a microparticle, whereinsaid niosome, liposome or microparticle comprise a homogeneous orheterogeneous mixture of the therapeutic agent.
 18. The implantablemedical device of claim 1, wherein the therapeutic agent is selectedfrom the group consisting of antithrombotic agents, antineoplasticagents, neoplastic agents, antiproliferative agents, antisensecompounds, immunosuppresants, angiogenic agents, angiogenic factors,antiangiogenic agents, and anti-inflammatory agents, or combinationsthereof.
 19. The implantable medical device of claim 1, wherein thetherapeutic agent is selected from the group consisting of2-chlorodeoxyadenosine, bivalirudin, Resten NG, and an oliogonucleotide.20. The implantable medical device of claim 1, wherein said therapeuticagent is an agent selected for treatment of restensosis or inflammation.21. The implantable medical device of claim 1, wherein the implantablemedical device is a stent.
 22. An implantable medical device comprising:an implantable device body having a plurality of holes; a therapeuticagent within the plurality of holes in the device body provided in atherapeutic agent layer; and a mixing layer provided in the plurality ofholes; wherein the therapeutic agent layer and the mixing layer containa concentration gradient of said therapeutic agent created by deliveringa mixing layer material without the therapeutic agent and liquefying aportion of the therapeutic agent layer with the mixing layer material,whereby the mixing layer has a smaller amount of therapeutic agentcontained therein than the therapeutic agent layer.
 23. The implantablemedical device of claim 22, wherein the mixing layer is apharmaceutically acceptable bioresorbable matrix that allows thetherapeutic agent contained within the therapeutic agent layer and themixing layer to be released as the matrix resorbs.
 24. The implantablemedical device of claim 23, wherein said bioresorbable matrix comprisesat least one pharmaceutically acceptable polymer.
 25. The implantablemedical device of claim 24, wherein said pharmaceutically acceptablepolymer is selected from the group consisting of polylactic acid,polyglycolic acid, polylactic-co-glycolic acid, polylacticacid-co-caprolactone, polyethylene glycol, polyethylene oxide, polylactic acid-block-poly ethylene glycol, poly glycolic acid-block-polyethylene glycol, poly lactide-co-glycolide-block-poly ethylene glycol,poly ethylene glycol-block-lipid, polyvinyl pyrrolidone, poly vinylalcohol, a glycosaminoglycan, polyorthoesters, polysaccharides,polysaccharide derivatives, polyhyaluronic acid, polyalginic acid,chitin, chitosan, chitosan derivatives, cellulose,hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose,polypeptides, polylysine, polyglutamic acid, albumin, polyanhydrides,polyhydroxy alkonoates, polyhydroxy valerate, polyhydroxy butyrate,proteins, polyphosphate esters, lipids, and mixtures thereof.
 26. Theimplantable medical device of claim 24, wherein the therapeutic agentlayer comprises at least one pharmaceutically acceptable polymerdifferent from the pharmaceutically acceptable polymer of the mixinglayer.
 27. The implantable medical device of claim 22, wherein thetherapeutic agent layer comprises the therapeutic agent and a watersoluble binding agent.
 28. The implantable medical device of claim 27,wherein the binding agent is a pharmaceutically acceptable polymerselected from the group consisting of poly ethylene glycol, polyethylene oxide, poly vinylpyrrolidone, poly vinyl alcohol, aglycosaminoglycan, polysaccharides, polysaccharide derivatives, polyhyaluronic acid, poly alginic acid, chitin, chitosan, chitosanderivatives, cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,carboxymethyl cellulose, poly peptides, poly lysine, poly glutamic acid,and proteins.
 29. The implantable medical device of claim 27, whereinsaid therapeutic agent is homogeneously dispersed as a solid solution insaid therapeutic agent layer.
 30. The implantable medical device ofclaim 27, wherein said therapeutic agent is homogeneously dispersed asmulti-phase mixture in said therapeutic agent layer.
 31. The implantablemedical device of claim 27, wherein said therapeutic agent isheterogeneously disposed in said therapeutic agent layer.
 32. Theimplantable medical device of claim 31, wherein said therapeutic agentis homogeneously or heterogeneously disposed in said therapeutic agentlayer as a solid particle dispersion, encapsulated agent dispersion, anemulsion, a suspension, a liposome, niosome, or a microparticle, whereinsaid niosome, liposome or microparticle comprise a homogeneous orheterogeneous mixture of the therapeutic agent.
 33. The implantablemedical device of claim 27, wherein said therapeutic agent from thetherapeutic agent layer is homogeneously dispersed as a solid solutionin said mixing layer.
 34. The implantable medical device of claim 27,wherein said therapeutic agent from the therapeutic agent layer ishomogeneously dispersed as multi-phase mixture in said mixing layer. 35.The implantable medical device of claim 27, wherein said therapeuticagent from the therapeutic agent layer is heterogeneously disposed insaid mixing layer.
 36. The implantable medical device of claim 35,wherein said therapeutic agent from the therapeutic agent layer ishomogeneously or heterogeneously disposed in said mixing layer as asolid particle dispersion, encapsulated agent dispersion, an emulsion, asuspension, a liposome, niosome, or a microparticle, wherein saidniosome, liposome or microparticle comprise a homogeneous orheterogeneous mixture of the therapeutic agent.
 37. The implantablemedical device of claim 22, wherein the therapeutic agent is selectedfrom the group consisting of antithrombotic agents, antineoplasticagents, neoplastic agents, antiproliferative agents, antisensecompounds, immunosuppresants, angiogenic agents, angiogenic factors,antiangiogenic agents, and anti-inflammatory agents, or combinationsthereof.
 38. The implantable medical device of claim 22, wherein thetherapeutic agent is selected from the group consisting of2-chlorodeoxyadenosine, bivalirudin, Resten NG, and an oliogonucleotide.39. The implantable medical device of claim 22, wherein said therapeuticagent is an agent selected for treatment of restensosis or inflammation.40. The implantable medical device of claim 22, wherein the implantablemedical device is a stent.
 41. A method for preparing an implantablemedical device, which method comprises: a) providing an implantablemedical device with a plurality of holes; b) loading into the pluralityof holes an amount of a liquified therapeutic agent, which amount issufficient to form a therapeutic agent layer; c) allowing said liquifiedtherapeutic agent layer to at least partially solidify; d) loading intothe plurality of holes an amount of a liquified bioresorbable polymerwhich amount is sufficient to liquify a portion of the therapeutic agentlayer, thereby allowing a portion of the therapeutic agent layer to bedisposed within a mixing layer; e) allowing said liquified bioresorbablepolymer and said portion of the therapeutic agent layer to solidify;wherein an amount of therapeutic agent contained within the mixing layerupon solidification is smaller than an amount of therapeutic agentcontained in the therapeutic agent layer; and further wherein steps dand e may optionally be repeated to form multiple mixing layers.
 42. Themethod for preparing an implantable medical device of claim 41, whereinthe liquified therapeutic agent is liquified by maintaining thetherapeutic agent at a temperature that is higher than its meltingpoint, or glass transition temperature.
 43. The method for preparing animplantable medical device of claim 41, wherein the liquifiedtherapeutic agent is formed by dissolving the therapeutic agent in asolvent.
 44. The method for preparing an implantable medical device ofclaim 41, wherein the liquified bioresorbable polymer is liquified bymaintaining the bioresorbable polymer at a temperature that is higherthan its melting point, or glass transition temperature.
 45. The methodfor preparing an implantable medical device of claim 41, wherein theliquified bioresorbable polymer is formed by dissolving thebioresorbable polymer in a solvent.
 46. The method for preparing animplantable medical device of claim 41, further comprising the step offorming a barrier layer by loading into the plurality of holes an amountof a liquified biocompatible polymer, which amount is sufficient to forma barrier layer, wherein the barrier layer is located adjacent thetherapeutic agent layer.
 47. The method for preparing an implantablemedical device of claim 46, wherein the liquified biocompatible polymeris liquified by maintaining the biocompatible polymer at a temperaturethat is higher than its melting point, or glass transition temperature.48. The method for preparing an implantable medical device of claim 46,wherein the liquified biocompatible polymer is formed by dissolving thebiocompatible polymer in a solvent.
 49. The method for preparing animplantable medical device of claim 41, wherein the liquefiedbioresorbable polymer loaded into the holes does not contain thetherapeutic agent.
 50. The method for preparing an implantable medicaldevice of claim 41, wherein the liquefied therapeutic agent layercomprises the therapeutic agent and a pharmaceutically acceptablepolymer.
 51. The method for preparing an implantable medical device ofclaim 50, wherein the liquefied therapeutic agent layer comprises fromabout 50% to about 95% therapeutic agent and from about 5% to about 50%pharmaceutically acceptable polymer.